Being one of the enzymes localized in endoplasmic reticulum, SCD is a rate determining enzyme of monounsaturated fatty acid synthesis, and introduces a double bond into the Δ9-Δ10 position of saturated fatty acid. SCD has selectivity for palmitic acid and stearic acid, and converts them to palmitoleic acid and oleic acid (J Biol. Chem. 1976 Aug. 25; 251(16): 5095-5103; Prog Lipid Res. 1995; 34(2): 139-150). The products resulting from these enzyme reactions are most abundantly contained in various fats such as phospholipid, triglyceride, cholesterol ester, wax ester and the like (Prostaglandins Leukot Essent Fatty Acids. 1995 October; 53(4): 279-286; J Lipid Res. 2002 December; 43(12): 2146-2154). In addition, monounsaturated fatty acid is not only a constituent factor of fat but also plays an important role as a mediator of intercellular signaling, cell differentiation, apoptosis and the like (Dev Neurosci. 1992; 14(1): 61-68; FEBS Lett. 1999 Jul. 2; 454(1-2): 42-46; J Lipid Res. 1999 September; 40(9): 1549-1558; Diabetes. 1999 October; 48(10): 2007-2014; Immunology. 2002 December; 107(4): 435-43; Proc Natl Acad Sci USA. 2003 Mar. 18; 100(6): 3077-3082). Since monovalent unsaturated fatty acid have a wide variety of functions, variation in the SCD activity is considered to possibly influence various metabolic pathways relating to diabetes, obesity, abnormal lipid metabolism, fatty liver, metabolic syndrome, arteriosclerosis-associated disease and cardiovascular disease.
As SCD genes, two types (SCD1, SCD2) in rat (GenBank ACCESSION No.: NM—139192; GenBank ACCESSION No.: NM—031841), and four types in mouse (SCDs 1, 2, 3, and 4) (GenBank ACCESSION No.: NM—009127; GenBank ACCESSION No.: NM—009128; GenBank ACCESSION No.: NM—024450; GenBank ACCESSION No.: NM—183216) are cloned.
SCD1 is expressed in various tissues, and characteristically regulated by dietary factor and hormone factor including insulin, cholesterol and polyvalent unsaturated fatty acid (Curr Opin Lipidol. 2003 June; 14(3): 255-261). In human, 2 kinds (SCD1 and SCD5) of genes have been cloned (GenBank ACCESSION NO.: NM—005063; GenBank ACCESSION NO.: NM—001037582), amino acid sequence homology between human SCD1 and mouse SCD1 is as high as 85% (Biochem J. 1999 May 15; 340 (Pt 1): 255-264; Gene. 2003 Apr. 24; 309(1): 11-21).
The SCD activity increases in human and animals with fatty liver, but deletion of SCD1 was found to improve both the high-fat diet induced fatty liver and hereditary fatty liver (Proc Natl Acad Sci USA. 2002 Aug. 20; 99(17): 11482-11486; J Biol Chem. 2000 Sep. 29; 275(39): 30132-30138). It has been confirmed that SCD1 lack mouse shows resistance to diet-induced obesity, promoted energy consumption, decrease in visceral fat, and enhanced insulin signal (Proc Natl Acad Sci USA. 2002 Aug. 20; 99(17):11482-11486; J Lipid Res. 2004 September; 45(9): 1674-1682; Proc Natl Acad Sci USA. 2003 Sep. 16; 100(19): 11110-11115).
SCD1/leptin double knockout mouse is significantly nonobese as compared to control leptin deficient mouse, and shows a remarkable increase in the energy consumption amount and a significant decrease in the liver triglyceride storage and VLDL production. Therefore, suppression of SCD1 expression is considered to be an important constituent factor of a metabolic action of leptin (Science. 2002 Jul. 12; 297(5579): 240-243).
Additionally, SCD1 is involved in the differentiation of adipocytes, and suggested to be also involved in food ingestion and lipolysis. Since inhibition of acetyl-CoA carboxylase 2, glycerol-3-phosphate acyltransferase, fatty acid synthase and the like involved in fatty acid synthesis cascade like SCD1 affords improvement of abnormal lipid metabolism and resistance to obesity (Science. 2001 Mar. 30; 291(5513): 2558-2559; Science. 2000 Jun. 30; 288(5475): 2299-2300; Proc Natl Acad Sci USA. 2002 Jul. 9; 99(14): 9498-9502; Nat Genet. 2000 May; 25(1): 6-7), control of cascade involving SCD1 is considered to be suitable as a target of disease treatment.
Metabolic syndrome drawing attention in these days refers to a syndrome where a single individual shows plural symptoms of abnormal lipid metabolism, high blood pressure, abnormal sugar metabolism and the like, resulting from common onset basis such as visceral fat accumulation, insulin resistance and the like. Thus, it is a pathology with a high onset risk of cardiovascular disease and type 2 diabetes (JAMA. 2001; 285: 2486-2497; Circulation 2004; 109: 433-438; Diabet. Med. 1998; 15: 539-553; The Journal of the Japanese Society of Internal Medicine 2005; 94: 188-203). According to the current guidelines, the basis of the treatment of metabolic syndrome is considered to be the improvement of lifestyle. Since prevention of the onset of cardiovascular events by the administration of statin medicaments and fibrate medicaments has been reported (Am J Transplant. 2005 December; 5(12): 2929-2936; Lancet. 2005 Nov. 26; 366(9500): 1849-1861), a novel medicament having an SCD inhibitory action targeting plural risk factors of metabolic syndrome is considered to be necessary also from the aspects of treatment efficiency and medical economy.
As a therapeutic drug for SCD-mediated diseases, patent document 1 (WO2006/034338) discloses a compound represented by the following formula:
whereinx and y are each independently 0, 1, 2 or 3;G is —C(R4)═, —C(R4)═C(R4)— or the like;J is N or C(R10);L and M are each independently —N═ or —C(R4)═, provided that when G is —C(R4)═ or —C(R4)═C(R4)—, then both L and M should not be —C(R4)═;V is a bond, —N(R1)— or the like;W is —N(R1)C(O)—, —C(O)N(R1)— or the like;R1 is a hydrogen atom or the like;R2 is a C1-12 alkyl group or the like;R3 is a hydrogen atom, a C1-12 alkyl group, C3-12 cycloalkyl, aryl, a C3-12 heterocyclic group, a poly-cyclic structure having 2 to 4 rings, or the like;R4 is independently a hydrogen atom or the like;R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently a hydrogen atom, a C1-3 alkyl group or the like; andR10 is independently a hydrogen atom or the like.
In addition, patent documents 2 to 16 (WO2006/086447; WO2006/034446; WO2006/034441; WO2006/034312; WO2006/034279; WO2005/011657; WO2005/011656; WO2005/011655; WO2005/011654; WO2005/011653; WO2006/101521; WO2006/125178; WO2006/125179; WO2006/125180; WO2006/125181) disclose compounds having a structure similar to those of the compound represented by the above-mentioned formula.
However, these documents do not disclose that the compound of the present invention is used as a SCD inhibitor.
Patent document 17 (WO2006/086445) discloses a method for the treatment of side effects of body weight gain associated with drug therapy, which comprises administering an SCD1 inhibitor.
Patent document 18 (WO2006/130986) discloses a compound represented by the following formula:
whereinX—Y is N—C(O) or the like;Ar is phenyl or the like;HetAr is an optionally fused 5-membered aromatic heterocycle; andR5, R6, R7, R8, R9, R10, R11 and R12 are each independently a hydrogen atom, a C1-3 alkyl group or the like.
However, this document does not disclose the compound of the present invention which is used as a SCD inhibitor.
Patent document 19 (WO2006/053024) discloses a lactam compound represented by the following formula:
whereinCy is aryl, heteroaryl or the like, each of which is optionally substituted;L is (CR12R13)q1 or the like;Q is —(CR1R2)m-A;A is aryl, heteroaryl or the like, each of which is optionally substituted;E is —(CR3aR3b)n1;R1 and R2 are each independently H or a C1-8 alkyl group;R3a and R3b are each independently H or the like;R4, R5, R6, R7, R8, R9, R10 and R11 are each independently H or the like;m is 0, 1, 2 or 3;R12 and R13 are each independently H or the like;n1 is 1, 2, 3 or 4;q1 is 0, 1 or 2; andr is 0, 1 or 2.
Patent document 20 (WO2001/042241) discloses a pyrimidine derivative represented by the following formula:
whereinA is a halogen atom, phenyl or the like;R1 is a hydrogen atom or the like;R2, R3 and R4 are each independently a halogen atom or the like; andQ is CH or N.
Patent document 21 (U.S. Pat. No. 4,624,952) discloses a heterocycle derivative represented by the following formula:
whereinX1 and X2 are each independently N or the like;Ar is an optionally substituted phenyl group; andR5 is a hydrogen atom or the like.
Patent document 22 (WO2000/023444) discloses a pyridopyrimidine derivative represented by the following formula:
whereinR1 and R2 are each independently a hydrogen atom or the like;R3 is an alkenyl group or the like;R4 is alkenyl, aryl, —RCRDRE or the like;RC is aryl, heterocycle or the like;RD is aryl, heterocycle or the like; andRE is void, or aryl, heterocycle or the like.
However, these documents do not disclose that these compounds are SCD inhibitors.
patent document 1: WO2006/034338
patent document 2: WO2006/086447
patent document 3: WO2006/034446
patent document 4: WO2006/034441
patent document 5: WO2006/034312
patent document 6: WO2006/034279
patent document 7: WO2005/011657
patent document 8: WO2005/011656
patent document 9: WO2005/011655
patent document 10: WO2005/011654
patent document 11: WO2005/011653
patent document 12: WO2006/101521
patent document 13: WO2006/125178
patent document 14: WO2006/125179
patent document 15: WO2006/125180
patent document 16: WO2006/125181
patent document 17: WO2006/086445
patent document 18: WO2006/130986
patent document 19: WO2006/053024
patent document 20: WO2001/042241
patent document 21: U.S. Pat. No. 4,624,952 specification
patent document 22: WO2000/023444